Synthesis of New Hematoporphyrin Derivatives Providing a Tumor-Specificity

已知血卟啉衍生物（Hp-D）在肿瘤组织中蓄积并发挥光动力学作用。但这是一种不稳定的复杂混合物，因此仍不确定哪种成分具有这些生物活性。双乙酸血卟啉(Hp-Ac, <C_（38)H_(42)O_8N_4>, NW 682）是碱处理前Hp-D的主要成分，而二酸血卟啉(Hp-Si, <C_（46)H_(66)O_6N_4Si_2>, MW 826）是碱处理前Hp-D的主要成分。合成了一种新化合物，并对其性能进行了验证。Hp-Ac和Hp-Si与Hp-D一样，在体外可以很好地融入人膀胱癌细胞，并通过静脉给药进入大鼠腹水肿瘤细胞。Hp-Ac、Hp-Si、Hp-D经静脉注射入荷瘤大鼠（is-iv）后，大体呈肝脏、脾脏>肿瘤、肾脏、肺>睾丸、肌肉组织分布的趋势。Hp-Ac和Hp-D在这些组织中的水平逐渐下降，而Hp-Si在注射后可保持较长时间，可达96小时。Hp-D和Hp-Si的肿瘤/周围肌肉的卟啉浓度比值（T/M比值）分别为2.7 ~ 7.5和3.7 ~ 6.6，表明这两种物质在肿瘤内的高蓄积。另一方面，Hp-Ac的T/M值保持在1.0 ~ 1.7的较低水平。本研究表明Hp-Si可能是一种具有高肿瘤亲和力的卟啉衍生物。由于Hp-Si是一种单一化合物，该物质既可作为光敏剂用于光辐射治疗，也可作为药物载体用于癌症化疗。

Hematoporphyrin derivative (Hp-D)is known to accumulate in tumor tissues and exert a photodynamic action. But this is an unstable complex mixture, so that it is still undetermined which component has these biological activities.Hematoporphyrin diacetate (Hp-Ac, <C_(38)H_(42)O_8N_4> , NW 682) a main component of Hp-D before alkali-treatment, and hematoporphyrin disilate (Hp-Si, <C_(46)H_(66)O_6N_4Si_2> , MW 826). a new compound, were synthesized as a single chemical agent and their properties were verified.Hp-Ac and Hp-Si, as like Hp-D, are well incorporated into human bladder cancer cells in vitro as well as into rat ascite tumor cells by intravenous administration.Hp-Ac, Hp-Si and Hp-D, after intravenous injection into tumor-bearing rats (is-iv), show in general a trend of tissue distrubution in the following order: liver, Spleen>tumor, Kidney, lung>testis, muscle. Hp-Ac and Hp-D levels in these tissues gradually decrease, while Hp-Si retains for a longer period of time up to 96 hours after injection. The tumor/surrounding muscle ratio of porphyrin concentraion (T/M ratio) ranges from 2.7 to 7.5 for Hp-D and from 3.7 to 6.6 for Hp-Si, indicating a high intratumorous accumlation of these two substances. On the other hand, T/M value of Hp-Ac remains at a low level ranging 1.0 to1.7.The present investigation indicates the possible usefulness of Hp-Si as a porphyrin derivative which has a high tumor affinity. Since Hp-Si is a single chemical compound, this substance may be used as a photosensitizer in photoradiation therapy but also as a drug carrier in tragenting cancer chemotherapy.